Age-related macular degeneration (AMD) is the leading cause of irreversible severe central visual loss in the aged population. Various studies suggest that AMD has a significant genetic component. Current evidence supports the hypothesis that gene variation causes a predisposition to the disease. In 2003, we initiated this project by recruiting advanced AMD patients and controls with normal retinas. Up to date, over 400 subjects have been enrolled and 80 histopathological cases with AMD hae been collected. We also received and analyzed 835 DNA samples from the Blue Mountain Eye Study in Australia and 534 DNA samples from AREDS. We are comparing the allelic frequencies of single nucleotide polymorphisms (SNPs) within candidate genes between AMD and control subjects followed by the functional studies of these SNPs by in vitro and/or in vivo experiments. Through this approach, we can identify genetic risk factors of AMD and understand the role of these gene variations in the pathogenesis of the disease. Based on the information obtained from the above experiments and recent literature, a genetically engineered animal has been generated to act as the disease model. In FY2007, we have accomplished the following: (1) completed 6,000 SNPs genotypes, (2) confirmed and refined the HtrA1 AMD association in 4 cohorts and reported at international and national scientific meetings, (3) published the characterization of the retinal lesions in Ccl2/Cx3cr1 double knock-out (DKO) mice - a murine model of AMD, (4) confirmed and published ARMS2 (LOC387715) association with AMD, (5) confirmed the involvement of ER protein in the pathogenesis of AMD, (6) started to apply the DKO animal model in intervention studies of the long-chain omega-3 fatty acid feeding and pharma-chaperone molecule gavarge, (7) established an immortalized retinal pigmented epithelium cell lines for future experiments.